Over 70 years ago the human cutaneous active vasodilator system (AVD) was first described; however, its mechanisms remain unclear today. The long-term goal of this project is to define the integrative physiological mechanisms that effect cutaneous active vasodilation during thermoregulatory reflex responses to hyperthermia. This will contribute to our understanding of the role of the cutaneous circulation in adaptation to hot environments and to understanding the increased morbidity and mortality of persons due to heat related illness in "heat waves". In addition to the specific benefits to be gained in understanding human thermoregulation, this project will add greatly to our understanding of how complex neural co-transmitter systems can control the cardiovascular system. Study of the AVD co-transmitter system that controls the cutaneous vasculature in humans can be used to gain insights into how co-transmitter neural control systems work. Gaining such knowledge directly from human beings in vivo could not be accomplished in any other human tissue, in vivo, without significant risk. The following specific aims will be explored: 1) To determine whether cutaneous AVD during heat stress is atropine-sensitive in cystic fibrosis patients. 2) To determine whether activation of VPAC1 and/or PAC1 receptors mediate cutaneous active vasodilation during hyperthermia. 3) To resolve whether muscarinic receptor activation by endogenous acetylcholine release contributes to increased nitric oxide levels during cutaneous active vasodilation in heat stress. 4) To resolve whether the nitric oxide required for cutaneous active vasodilation is produced by endothelial nitric oxide synthase (eNOS) and/or by neuronal nitric oxide synthase (nNOS) during heat stress. 5) To define the role of cAMP in cutaneous active vasodilation during heat stress. 6) To define the role of cGMP in cutaneous active vasodilation during heat stress. Studies will be done in healthy humans and patients with cystic fibrosis. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the cholinergic, neuropeptidergic, nitric oxide, and second messenger systems. Laser-Doppler flowmetry will monitor skin blood flow responses during normothermia and hyperthermia at both drug-treated, experimental sites, and at adjacent untreated, control sites. In addition, intradermal microdialysis will be combined with measurements of bioavailable NO by NO-selective amperometric electrode to define further how the NO system functions in cutaneous active vasodilation.